Project Summary This application is being submitted in response to PAR-17-150 entitled Mechanisms of Disparities in Chronic Liver Diseases and Cancer. Since 1980, the incidence of hepatocellular carcinoma (HCC) has tripled, becoming one of the fastest rising cancers globally and in the US. HCC is now the second leading cause of cancer-related death worldwide. This increase in HCC-related incidence and mortality disproportionally affects racial/ethnic minority populations: African Americans have a two-fold higher incidence of liver cancer than Whites in the US. Because HCC mortality occurs earlier than other solid cancers, the potential years of life lost to HCC is substantial. While ethnic disparities have been reported for multiple cancers, less is understood about disparities in HCC. First, established risk factors for HCC are exposure to aflatoxins, alcohol, cirrhosis, and infection with hepatitis B virus (HBV) and hepatitis C virus (HCV). However, the variation in the prevalence of these factors by race/ethnicity cannot fully explain the steep increase in the incidence and the widening of race/ethnic gap. Second, exposure to environmental chemicals, including cadmium (Cd), has been associated with HCC in animal models; however, the Cd doses examined were much higher than non-occupational exposures observed in the general population. Recent data indicate that adverse health effects, including cancer, may occur at lower exposure levels than previously thought but this has not been adequately investigated for HCC. Third, data from genome-scale DNA methylation studies suggest that there are widespread epigenetic ?signatures? or changes that accompany both hepatic fibrosis progression and tumor development. However, these promising data derive from resected or transplanted liver which comprises only ~20% of HCC cases, and AAs are less likely to undergo surgery. Thus, the underlying mechanisms for disparities in HCC and poorer outcomes in these populations are still unknown. Our goal is to use a multidisciplinary approach to determine if cadmium exposure alone or as a part of a mixture (that includes lead, essential metals including zinc, selenium, manganese, magnesium and/or calcium) increase risk of HCC. We will determine if associations vary by ethnicity. To accomplish this, we will conduct a population-based case control study comprising 200 African Americans and 200 whites using the North Carolina Cancer registry to identify primary HCC cases. We will use mass spectrometry to measure urinary cadmium and other metals to estimate chronic exposure. We will then determine if regulatory sequences of previously identified cadmium associated methylation mediate the relationship between Cd exposure and HCC risk. Longer term, our vision is to identify epigenetic marks in accessible tissues that can be used to develop algorithms for early detection of HCC to improve outcomes. We anticipate that with this improved understanding of the integrated exposure, sociodemographic and molecular data that we will be better poised to combat and prevent the rise in HCC, particularly in minorities and the underserved.